Medicinal tablet



Patented June 9, 1925i.

iszaUoEK.-` WISEMAN, `or INDIANAPOLIS, INDIANA, assIeNoa To ELI LILLY ANn COMBANY; or INDIANAPOLIS, INBIANA, a. CORPORATION or INDIANA'.-

MEDICINAL martiri,`

TQLZZ ,Milioni t may concierne: l

.B a knew aaai, Bruce K. Wismar, acitlizen of the United States, residing at Indiaiiapolisin the county of Marion vand 6 State. of Indiana, have .invented a new and useful Medicinal Tablet, of ,which the folimag.isjaispeeifieaiot.

` Ifis `the.objeetoff my inventionto pro-` duce `a yfuedicnalytablet, and especially a hypodeimic l tablet, `which has materially greater solubility, is more quickly soluble, and hasgmore, nearly uniform solubility'at `d'll'ei'ei'it ftem ieraiilures vthan is the caseV i l?l a iyith such tablets noir in use; so that the 4tablet.maybe more comiqletely'dissolved, may be more quickly dissolved, may bedissolvednin a smaller `quantity' oi: Water if for ny `r'ea'soirthat, is desired, and may be disso vedwith nearlyequal facility in cold yvafuel andinhot Water. i i y. `This,makesiit possible to prepare a hypo- .dermic injection morequick'ly, with greater assurance. of complete solution, and with ir/.aterL of" any* temperature. By reason lioluiclvs'olution, on account `of the 'inn creased `speed of solubility ,of the tablet, thereisaivery material advantage, espe-` ,ei'ally in emergency eases, When quick action Withoutzthe loss oi an eXtra second is V.re-quired on the part of the physician. 1 11i ical-frying out my invention, I make the vtablet of a mixture ofthe desired drug ,'(aiyw`drug) `vvit'ha carrier or diluent in anysuitable `proportions,j but instead using the ordinary ormL `(the,hydrate) "of afctseL `01' .milk sugarY as such carrier or Hiluenu. I use' ya formzof` lactose or milk sugar which `gives thevad'vantages above set forth.

,',Ilyiere are sei/eral forms of `milk sugar `suitable for thisfallof `which `are substantially Without that -ivater of crystallization ,"which requires heating materially above the `boiling Point of Water in order to be .difiyen off. Theseare:

l.` The .4Q-anhydride 2. rllhe faz-anhydride. y The aarihydride Which, though it has taken Y'uio `'Water,permits such `water to be 4substantiallydriven off by heatingto the boiling point V,of fwater` or. very slightly abolifeiit.m y y l 1 y V `14am`mixtureoifsome or -aljlolf `formsv l,

ppilication `filed February 18, 1924i. Serial No. 6793,-5VJG`.

The aus of mui: sugarwhich referees the mixture of the ocearihydride and" (fanhydride, *with a second preference ffor the -ahhydride over` the afanhyidri'de; but goed results cany be` secured by the use .of any of the three forms noted for a iiiiitue of vtwo or more olf them. 1 f y lt has heretofore been universal practice, so far am` aware, use the `hydrate Lform 'offmilk "sugar or laetose as 4the earrier or diluent in the manufacture of me'- dicinal tablets, and especially offhy'poder'- mie tablets. Such lactose hydrate is Athe ordinary form of milk sugar; and is the one formed by crystallization from ,Water solution normal temperatures.A When it crystallizes, it. has one `molecule lof Water" of crys'talliaation, or about 5% Weight. The Water `.of crystallization in ordihaiy milk sugarffor lactosel hydrate is so firmly heldthat yity requires heatingto ,about 1250 `or 1300., C. to drive it olif. This lactose hydrate hasa Widely variable solubility ,i'r'ifth YVariations 4in temperature, and' one which at Anormal temperatures islow in comparison yith that oit lthe severalforms of milk sugar I referred ,to ,above The initialfsolubility oflactosehydrate varies `from about 4.8 parts per 100 at the freezing point Water to about parts lper l() at the boiling point of Water, and fis about. parts per 1001.51.13 `blood temperature; These "iglures are those given by Hudson in the iroceed gings of the American Chemical IV'ol. 30, No. f?, page 1757. .y y

The `@anhydride of milk sugar hasmuch greater solubility. in cold Water, and yin Wlaterfat or .near blood temperature, ,than

"Society, i

has the hydrate form, and it has materially y greater initial solubility in Waterfatall temperatures, even hot" Water, than `has the lhydrate `form; and `it 'has` more'nearly uni form solubility at different temperatures. The initial solubility oit the danhydride varies from about 3l parts per 100 at'fthe freezing' point offri/atei' v only to about 49 parts per 100 fat` the Iboiling point vof Water, ,andis about 36 partsper 100 at blood temfloerature,

A similar comparison `also ,exists for final solubilities, though "With Adifferent ratios, With .the `@anhydride haying .greater inal solubility at all temperatures belo`vv93o C.; i but as `only initial solubilities Yare ordinarily material in medicinal tablets, and especially hypodermic tablets, I have not given in detail the comparison ol final solubilities.

These comparative initial solubilities make for the quicker and more complete solution ot' the -anhydride than of the hydrate in water at all temperatures; and particularly so at all temperatures at which water is normally obtainable and at which it can be used for either oral or hypodermic administration. Further, the initial solubility of the -anhydride is more nearly uniform throughout the entire range of water temperatures than is that of the hydrate; for the initial solubility ot the -anhydride varies less than 1-110- times the value i at O for variations between 0o and 100o C..

while the initial solubility of the hydrate varies over l1 times.

The figures given above are not intended to be absolutely exact. They indicate in a general way, and I think with fair exactness, what the conditions are. They show clearly the greater solubility of the -anhydride under all conditions of normal administration. Further, they show the greater uniformity i the solubility of the -anhydride throughout the temperature range.

I think it unnecessary to give specific comparisons involving the other forms of lactose which my broad invention contemplates. It suffices to say that all these forms have much greater initial solubility than has the hydrate, and have more uniform solubility throughout the working temperature-range than has the hydrate.

The forms of milk sugar which my invention contemplates may be obtained in various ways:

The -anhydride may be obtained by evaporation to dryness of a water-solution of ordinary milk sugar at a temperature eX- ceeding 93 C.; and when thus formed is quite stable and does not deliquesce. It theevaporation of the water-solution of ordinary milk sugar todryness is carried on below 93 C., it is the ordinary hydrate form of milk sugar which crystallizes out, with about 5% by weight (or 1 molecule) 'of water of crystallization.

To prepare the (7c-anhydride, the crystals oli the hydrate are heated at about 130o C. for several hours, to drive otl' the water of crystallization.

If the @anhydride is allowed to stand tor a few days, it takes up water from the air, to about 4% by weight. This water is apparently not combined with the milk sugar in the same way as is the water of crystallization in the ordinary lactose hydrate, for instead of requiring heating to about 125 to 1300 C. to drive it off it can be driven off by heating to about 100 to 105 C., which is hardly over the boiling point of water.

This 4% by weight of water which the os-anhydride takes up from the air on standing is less than that represented by one molecule ot water of crystallization, and is the greatest amount ot' water present in any o1 the forms of milk sugar which my invention contemplates as a carrier or diluent in making medicinal tablets.

The solutions of the -anhydride and ot' the cac-anhydride have different initial optical rotation. The rra-anhydride, like ordinary lactose hydrate, when lirst dissolved, has an optical rotation of about 86o; but this rotation is not constant, and in the course of a day or so diminishes to about The l-anhydride, on the other hand, when lirst dissolved, has an optical rotation of only about 360; but this rotation is also not constant, and in the course of a day or so changes to about o. Probably when the lina-l value of the optical rotation has been attained the solution contains equilibrium amounts of the -anhydride and olf either the oc-anhydride or the hydrate. 7^ This mutarotation is one way of distinguishing the `f5-anhydride from the -anhydride and l'rom the hydrate.

It' desired. mixtures of the a-anhydride and the {JJ-anhydride may be made in any manner tor use in accordance with my invention. This may be by mechanical miX- ing. However, l prefer to use a mixture which is primarily obtained in equilibrium proportions, and free from optical mutarotation. Such a mixture in equilibrium proportions may be obtained by precipitating the sugar from a boiling water-solution by the addition thereto of lour or tive volumes of boiling alcohol, preferably alcohol of at least 95% concentration. The crystals thus thrown down are apparently in equilibrium proportions, in that their solution is initially free from optical mutarotation. Such crystals may contain a small quantity of the hydrate, for I find that there is sometimes some combined water, usually less than 1% by weight. In no case do such crystals thus thrown down contain as much as 21/2% by weight ot' water which requires heating to 125 C. in order to be driven off.

None of the forms of milk sugar contemplated by my invention contain as much as 21/2 by weight of water which cannot be driven ott' at 105 C.; and in none of them does the total water exceed 4% by weight; and in any of them there is less water than that represented by one molecule of water of crystalization.

In making tablets in accordance with my invention, I mix the desired drug in any desired proportion with the form or forms ot' milk sugar which my invention contemplates. These proportions are varied in accordance with the nature of the drug, and in accordance with the size of the dose per tablet; but in substantially all instancesthe quantity of lactose Will be many times greater than the `quantity or the drug. Ordinarily,`the amount of the lactose will exceed 95% of the complete tablet, and in many cases Will exceed 99%. At'ter themixture in the Y desired proportions has been made, in the same Way that it is noiv made when lactose hydrate is used, the tablets are molded in any usual or convenient manner,`

and are ready for quick use Where needed.

I do not claim to have discovered the anhydrides of milk` sugar. rl`hese have been known for twenty or thirty years at least, (with the possible exception of the equilibrium mixture obtained by precipitation with boiling alcohoh) and their properties have been` investigated. Nevertheless, the universal practice has been to make medicinal tablets, and especially hypodermic tablets, with a carrier or diluent of lactose hydrate, in contradistinction to my'present invention. Y f

l claim `as my invention l. A medicinal tablet, comprising a mixture of the desired drug with a form of lactose containing less than Z1/2% by Weight of water Which cannot be driven oil at 105 C.

2. A medicinal tablet, comprising a mixture of a desired drug With a form of lactosc containing not to exceed 4% by Weight oit Water.

A medicinal tablet, comprising` a mixture ot' a desired drug with a form of lactose containing less Water than that represented -by one molecule of Water of crystallization.l

A medicinal tablet, comprising a mixtu re or a desired drug With a form of lactose ol which at least part is a lactose anhydride.

5. A medicinal tablet, comprising` a mixture or a desired drug with a form of lactoseV ot' which at least part is the -anhydride or milk sugar.

6. A medicinal tablet, comprising a mixture of a desired drug with a form of lactose containing the @-anhydride and -anhydride mixed.

7. A medicinal tablet, comprising a mixture of a desired drug with a form of lactose containing the oa-anhydride and {Ji-anhydride mixed in equilibrium proportions.

8. A medicinal tablet having its body portion comprised of an anhydride of milk sugar to facilitate the increased solubility or' the same. i

in Witness whereof, I have hereunto set my hand at Indianapolis, Indiana, this 13th day of February, A. D. one thousand nine hundred and twenty-four.

BRUCE K. WISEMAN. 

